Pharmaceutical composition comprising (1r,4r)-6′-flouro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4,b]indol]-4-amine and a propionic acid derivative

ABSTRACT

The invention relates to a pharmaceutical composition comprising a first pharmacologically active ingredient, which is selected from (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and the physiologically acceptable salts thereof, and a second pharmacologically active ingredient, which is a propionic acid derivative selected from the group consisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, fenbufen, suprofen, pirprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, flunoxaprofen, alminoprofen, naproxcinod, and the physiologically acceptable salts thereof.

The invention relates to a pharmaceutical composition comprising a firstpharmacologically active ingredient, which is selected from(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand the physiologically acceptable salts thereof, and a secondpharmacologically active ingredient, which is a propionic acidderivative selected from the group consisting of ibuprofen, naproxen,ketoprofen, flurbiprofen, fenoprofen, fenbufen, suprofen, pirprofen,indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, flunoxaprofen,alminoprofen, naproxcinod, and the physiologically acceptable saltsthereof.

(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′pyrano[3,4,b]-indol]-4-amineand its corresponding physiologically acceptable salts as well asmethods for their preparation are well known, for example, fromWO2004/043967 and WO2008/040481. The compounds exhibit analgesicproperties and are particularly suitable for the treatment of acute,visceral, neuropathic or chronic (nociceptive) pain.

The propionic acid derivatives may preferably be regarded as NSAIDs,i.e. non-steroidal anti-inflammatory and antirheumatic drugs, bearingthe common structural feature of propionic acid, and are used for thetreatment of various pain conditions, in particular inflammatory pain.

Though both of the aforementioned substance classes can be used for theprevention and treatment of pain and are as such therapeuticallyeffective, side effects may occur, especially upon prolonged use or whenadministered at high dosages.

It is further known that specific combinations of pharmacologicallyactive compounds exert supra-additive (synergistic) therapeutic effectsupon administration. An advantage of these special cases is that theoverall dose and accordingly the risk of undesired side effects may bereduced.

In a further aspect, two pharmacologically active compounds exerting asynergistic effect may be combined in one single pharmaceutical dosageform, e.g. a tablet, thus enhancing patient compliance.

It is an object of the invention to provide pharmaceutical compositionswhich have advantages compared to pharmaceutical compositions of theprior art. In particular, the pharmaceutical compositions should providerapid therapeutic effects, but also should have a high tolerability,good compliance and safety.

This object has been achieved by the subject-matter of the patentclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the withdrawal threshold in g in dependence of the timeelapsed after administration.

FIG. 2 shows the graphical analysis of experimental ED₂₅-valuescorresponding to the single administration of the firstpharmacologically active ingredient and ibuprofen as the secondpharmacologically active ingredient, respectively, and the correspondingtheoretic additive values for the combined administration of the firstand the second pharmacologically active ingredient compared to theexperimental ED₂₅-values determined for said combination.

FIG. 3 shows the graphical analysis of experimental ED₅₀-valuescorresponding to the single administration of the firstpharmacologically active ingredient and ibuprofen as the secondpharmacologically active ingredient, respectively, and the correspondingtheoretic additive values for the combined administration of the firstand the second pharmacologically active ingredient compared to theexperimental ED₅₀-values determined for said combination.

It has been surprisingly found that a pharmaceutical compositioncomprising(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand a propionic acid derivative is useful for the treatment of pain,especially chronic inflammatory pain, or acute or non-chronicpostoperative (postsurgical) pain.

Further it has been surprisingly found that said composition exhibits asynergistic therapeutic effect upon administration. Therefore, theoverall administered dose may be lowered, so that fewer undesiredside-effects will occur.

A first aspect of the invention relates to a pharmaceutical compositioncomprising:

-   -   a) a first pharmacologically active ingredient selected from        (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine        and the physiologically acceptable salts thereof, and    -   b) a second pharmacologically active ingredient, which is a        propionic acid derivative selected from the group consisting of        ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen,        fenbufen, suprofen, pirprofen, indoprofen, tiaprofenic acid,        oxaprozin, ibuproxam, flunoxaprofen, alminoprofen, naproxcinod,        and the physiologically acceptable salts thereof.

The pharmaceutical composition according to the invention comprises afirst pharmacologically active ingredient selected from(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand the physiologically acceptable salts thereof.

For the purpose of specification,(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineis the compound according to formula (I) which can also be referred toas1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole(trans)

The definition of the first pharmacologically active ingredient includes(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I), inany possible form including solvates, cocrystals and polymorphs, and itsphysiologically acceptable salts, in particular acid addition salts andcorresponding solvates, cocrystals and polymorphs.

The pharmacologically active ingredient(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminemay be present in the pharmaceutical composition according to theinvention in form of a physiologically acceptable salt, preferably anacid addition salt, whereby any suitable acid capable of forming such anaddition salt may be used.

The conversion of(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineinto a corresponding addition salt, for example, via reaction with asuitable acid may be effected in a manner well known to those skilled inthe art. Suitable acids include but are not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formicacid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelicacid, fumaric acid, lactic acid, citric acid, glutamic acid and/oraspartic acid. Salt formation is preferably effected in a solvent, forexample, diethyl ether, diisopropyl ether, alkyl acetates, acetoneand/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solutionis also suitable for the preparation of hydrochlorides.

In a preferred embodiment, the first pharmacologically active ingredientis(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I).

In another preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of a physiologically acceptable acid addition salt, inparticular the hydrochloride, hemicitrate or maleate salt.

Unless explicitly stated otherwise, all amounts of the firstpharmacologically active ingredient specified in the following are givenaccording to the corresponding amount of(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I).

The pharmaceutical composition according to the invention comprises asecond pharmacologically active ingredient, which is a propionic acidderivative selected from the group consisting of ibuprofen, naproxen,ketoprofen, flurbiprofen, fenoprofen, fenbufen, suprofen, pirprofen,indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, flunoxaprofen,alminoprofen, naproxcinod, and the physiologically acceptable saltsthereof.

The definition of the second pharmacologically active ingredientincludes the aforementioned propionic acid derivatives in any possibleform including any enantiomers, if applicable, carboxamides, solvates,prodrugs, cocrystals and polymorphs, and their physiologicallyacceptable salts, in particular acid addition salts and correspondingsolvates, cocrystals and polymorphs.

The preferred propionic acid derivatives according to the inventionpreferably contain free carboxylic groups, and additionally, may containnitrogen functionalities. Thus, the conversion into a salt may beeffected in a manner well known to those skilled in the art, forexample, via reaction with a suitable base, but as well with an acid ormetal salt. Suitable bases include but are not limited to the hydroxidesof sodium, potassium, calcium and/or magnesium. Suitable acids includebut are not limited to hydrochloric acid, hydrobromic acid, sulfuricacid, methanesulfonic acid, formic acid, acetic acid, oxalic acid,succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid,citric acid, glutamic acid and/or aspartic acid. Moreover,trimethylchlorosilane in aqueous solution is also suitable for thepreparation of hydrochlorides. Suitable metal salts include but are notlimited to alkali salts such as sodium, potassium or lithium phosphate,sulfate, methanesulfonate, formate, acetate, oxalate, succinate,tartrate, mandelate, fumarate, lactate, citrate, glutamate, aspartateand/or silyls, as well as alkaline earth salts, in particular magnesiumand calcium salts, including their phosphate, sulfate, methanesulfonate,formate, acetate, oxalate, succinate, tartrate, mandelate, fumarate,lactate, citrate, glutamate, aspartate and/or silyl salts. Saltformation is preferably effected in a solvent, for example, diethylether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone.

As prodrugs of the preferred propionic acid derivatives, amides, esters,in particular nitroxybutyl esters, and N-hydroxy carboxamides areespecially preferred. Suitable methods for selecting and preparing aprodrug of a given substance are, for example, described in “Textbook ofDrug Design and Discovery”, 3^(rd) edition, 2002, chapter 14, pages410-458, Editors: Krogsgaard-Larsen et al., Taylor and Francis.

The second pharmacologically active ingredient is a propionic acidderivative selected from the group consisting of ibuprofen, naproxen,ketoprofen, flurbiprofen, fenoprofen, fenbufen, suprofen, pirprofen,indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, flunoxaprofen,alminoprofen, naproxcinod, and the physiologically acceptable saltsthereof.

In a preferred embodiment, the second pharmacologically activeingredient is an aryl propionic acid derivative selected from the groupconsisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen,suprofen, pirprofen, indoprofen, ibuproxam, flunoxaprofen, alminoprofen,naproxcinod, and the physiologically acceptable salts thereof.

In another preferred embodiment, the second pharmacologically activeingredient is an aryl propionic acid derivative selected from the groupconsisting of ibuprofen, ibuproxam, suprofen, indoprofen, alminoprofen,and the physiologically acceptable salts thereof.

Unless explicitly stated otherwise, all amounts of the secondpharmacologically active ingredient specified in the following are givenaccording to the corresponding amount of the free compound, i.e. in formof the free carboxylic acid.

In a preferred embodiment, the second pharmacologically activeingredient is a propionic acid derivative in form of the free compound.

In another preferred embodiment, the second pharmacologically activeingredient is an aryl propionic acid derivative in form of the freecompound.

In still another preferred embodiment, the second pharmacologicallyactive ingredient is an aryl propionic acid derivative in form of itssodium salt.

In a preferred embodiment, the second pharmacologically activeingredient is ibuprofen.

In a preferred embodiment, the first pharmacologically active ingredientis(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I),and the second pharmacologically active ingredient is a propionic acidderivative.

In another preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I),and the second pharmacologically active ingredient is an aryl propionicacid derivative.

In still another preferred embodiment, the first pharmacologicallyactive ingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I),and the second pharmacologically active ingredient is an aryl propionicacid derivative in form of the respective sodium salt.

In yet another preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I),and the second pharmacologically active ingredient is ibuprofen,preferably in form of the carboxylic acid.

In a further preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of a physiologically acceptable acid addition salt, inparticular the hydrochloride, hemicitrate or maleate salt, and thesecond pharmacologically active ingredient is ibuprofen, preferably inform of the carboxylic acid.

Since the second pharmacologically active ingredient contains a carboxylgroup, it may react with the first pharmacologically active ingredientaccording to formula (I) forming a salt which incorporates bothpharmacologically active ingredients.

Thus, in another preferred embodiment, the pharmaceutical compositionaccording to the invention comprises the first and the secondpharmacologically active ingredient in form of a salt formed from thesetwo pharmacologically active ingredients. Such a salt formation may bepartial, i.e. the pharmaceutical composition according to the inventioncomprises one or both of these pharmacologically active ingredients alsoin their non-salt form, or the salt formation may essentially becomplete.

Another aspect of the invention relates to a pharmaceutical dosage formcomprising the pharmaceutical composition according to the invention.

The first and the second pharmacologically active ingredient aretypically contained in the pharmaceutical dosage form according to theinvention in a therapeutically effective amount. The amount thatconstitutes a therapeutically effective amount varies according to thepharmacologically active ingredients, the condition being treated, theseverity of said condition, the patient being treated, and whether thepharmaceutical dosage form is designed for an immediate or controlledrelease.

In a preferred embodiment, the content of the first pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at most 10 wt.-% or at most 5 wt.-% or at most 3 wt.-%or at most 1.0 wt.-%, more preferably at most 0.8 wt.-%, yet morepreferably at most 0.5 wt.-%, still more preferably at most 0.2 wt.-%,even more preferably at most 0.1 wt.-%, most preferably at most 0.05wt.-%, and in particular at most 0.01 wt.-% or at most 0.005 wt.-% or atmost 0.001 wt.-%.

In a preferred embodiment, the content of the second pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at most 95 wt.-%, more preferably at most 80 wt.-%, yetmore preferably at most 70 wt.-%, still more preferably at most 60wt.-%, even more preferably at most 55 wt.-%, most preferably at most 50wt.-%, and in particular at most 45 wt.-%.

In a preferred embodiment, the content of the first pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at least 0.0001 wt.-%, more preferably at least 0.0003wt.-%, yet more preferably at least 0.0005 wt.-%, still more preferablyat least 0.0008 wt.-%, even more preferably at least 0.001 wt.-%, mostpreferably at least 0.003 wt.-%, and in particular at least 0.005 wt.-%.

In a preferred embodiment, the content of the second pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at least 0.1 wt.-%, more preferably at least 0.5 wt.-%,yet more preferably at least 1 wt.-%, still more preferably at least 3wt.-%, even more preferably at least 5 wt.-%, most preferably at least7.5 wt.-%, and in particular at least 10 wt.-%.

Unless explicitly stated otherwise, in the meaning of the invention theindication “wt.-%” shall mean weight of the respective ingredient pertotal weight of the pharmaceutical dosage form or per total weight ofthe pharmaceutical composition, respectively.

Preferably, in the pharmaceutical dosage form according to the inventionand the pharmaceutical composition according to the invention,respectively, the relative weight ratio of the first pharmacologicallyactive ingredient to the second pharmacologically active ingredient iswithin the range of from 1:2 to 1:1,000,000, more preferably 1:30 to1:1,000,000, most preferably 1:100 to 1:1,000,000, and in particular1:1,000 to 1:500,000.

In a preferred embodiment, in the pharmaceutical dosage form accordingto the invention and the pharmaceutical composition according to theinvention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100 to 1:10,000, morepreferably 1:200 to 1:7,500, still more preferably 1:500 to 1:5,000,most preferably 1:750 to 1:2,500, and in particular 1:900 to 1:2,000.

In another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:1,000 to 1:100,000, morepreferably 1:2,000 to 1:80,000, still more preferably 1:4,000 to1:50,000, yet more preferably 1:6,000 to 1:20,000, most preferably1:8,000 to 1:15,000, and in particular 1:9,000 to 1:12,500.

In still another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:5,000 to 1:500,000, morepreferably 1:10,000 to 1:400,000, still more preferably 1:20,000 to1:300,000, most preferably 1:40,000 to 1:250,000, and in particular1:50,000 to 1:200,000.

In yet another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100,000 to 1:900,000,more preferably 1:250,000 to 1:800,000, still more preferably 1:300,000to 1:700,000, most preferably 1:350,000 to 1:650,000, and in particular1:400,000 to 1:600,000.

In a further preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100,000 to 1:1,000,000,more preferably 1:250,000 to 1:980,000, still more preferably 1:500,000to 1:960,000, most preferably 1:600,000 to 1:950,000, and in particular1:700,000 to 1:900,000.

Preferably, in the pharmaceutical dosage form according to the inventionand the pharmaceutical composition according to the invention,respectively, the relative molar ratio of the first pharmacologicallyactive ingredient to the second pharmacologically active ingredient iswithin the range of from 1:2 to 1:1,000,000, more preferably 1:10 to1:1,000,000, and most preferably 1:500 to 1:1,000,000.

In a preferred embodiment, in the pharmaceutical dosage form accordingto the invention and the pharmaceutical composition according to theinvention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:10 to 1:1000, morepreferably 1:20 to 1:750, still more preferably 1:50 to 1:500, mostpreferably 1:75 to 1:250, and in particular 1:90 to 1:200.

In another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100 to 1:10,000, morepreferably 1:200 to 1:7,500, still more preferably 1:500 to 1:5,000,most preferably 1:750 to 1:2,500, and in particular 1:900 to 1:2,000.

In still another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:1,000 to 1:100,000, morepreferably 1:2,000 to 1:80,000, still more preferably 1:4,000 to1:50,000, yet more preferably 1:6,000 to 1:20,000, most preferably1:8,000 to 1:15,000, and in particular 1:9,000 to 1:12,500.

In yet another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:5,000 to 1:500,000, morepreferably 1:10,000 to 1:400,000, still more preferably 1:20,000 to1:300,000, most preferably 1:40,000 to 1:250,000, and in particular1:50,000 to 1:200,000.

In a further preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100,000 to 1:900,000,more preferably 1:250,000 to 1:800,000, still more preferably 1:300,000to 1:700,000, most preferably 1:350,000 to 1:650,000, and in particular1:400,000 to 1:600,000.

In still a further preferred embodiment, in the pharmaceutical dosageform according to the invention and the pharmaceutical compositionaccording to the invention, respectively, the relative molar ratio ofthe first pharmacologically active ingredient to the secondpharmacologically active ingredient is within the range of from1:100,000 to 1:1,000,000, more preferably 1:250,000 to 1:980,000, stillmore preferably 1:500,000 to 1:960,000, most preferably 1:600,000 to1:950,000, and in particular 1:700,000 to 1:900,000.

The amounts of the first and the second pharmacologically activeingredient contained in the pharmaceutical dosage form according to theinvention may vary depending on different factors well known to thoseskilled in the art, for example, the weight of the patient, the route ofadministration, the severity of the illness and the like.

In general, both pharmacologically active ingredients contained in thepharmaceutical dosage form according to the invention may beadministered in amounts up to their maximum daily dose, which is knownto those skilled in the art. For example, as the secondpharmacologically active ingredient, ibuprofen may preferably beadministered to a patient in a maximum daily dose of up to 3,200 mg.

When administered in the prescribed manner, e.g. once daily or twicedaily, the pharmaceutical dosage form according to the invention and thepharmaceutical composition according to the invention, respectively,preferably contain the first and the second pharmacologically activeingredient, independently of one another, in an amount corresponding to75±15 wt.-%, 75±10 wt.-%, 75±5 wt.-%, 50±15 wt.-%, 50±10 wt.-%, 50±5wt.-%, 25±15 wt.-%, 25±10 wt.-% or 25±5 wt.-% of the respective maximumdaily dose of the first and the second pharmacologically activeingredient, respectively.

Preferably, the pharmaceutical dosage form according to the inventioncontains the first pharmacologically active ingredient in a dose of from0.1 μg to 5,000 μg, more preferably, 0.1 μg to 2,500 μg, still morepreferably 1.0 μg to 1,000 μg, yet more preferably 10 to 800 μg, mostpreferably 15 μg to 600 μg, and in particular 20 μg to 440 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains the first pharmacologically active ingredient ina dose within the range of 13±12 μg, more preferably 13±10 μg, stillmore preferably 13±8 μg, yet more preferably 13±6 μg, even morepreferably 13±5 μg, most preferably 13±4 μg, and in particular 13±3 μg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 20±15 μg, more preferably 20±13μg, still more preferably 20±12 μg, yet more preferably 20±10 μg, evenmore preferably 20±8 μg, most preferably 20±6 μg, and in particular 20±5μg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 40±35 μg, more preferably 40±30μg, still more preferably 40±25 μg, yet more preferably 40±20 μg, evenmore preferably 40±15 μg, most preferably 40±10 μg, and in particular40±5 μg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 60±50 μg, more preferably 60±40μg, still more preferably 60±30 μg, yet more preferably 60±20 μg, mostpreferably 60±10 μg, and in particular 60±5 μg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 80±70 μg, more preferably 80±60μg, still more preferably 80±50 μg, yet more preferably 80±40 μg, evenmore preferably 80±20 μg, most preferably 80±10 μg, and in particular80±5 μg.

In still a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 100±90 μg, more preferably100±80 μg, still more preferably 100±60 μg, yet more preferably 100±40μg, even more preferably 100±20 μg, most preferably 100±10 μg, and inparticular 100±5 μg.

In yet a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 120±100 μg, more preferably120±80 μg, still more preferably 120±60 μg, yet more preferably 120±40μg, even more preferably 120±20 μg, most preferably 120±10 μg, and inparticular 120±5 μg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 150±90 μg, more preferably150±80 μg, still more preferably 150±60 μg, yet more preferably 150±40μg, even more preferably 150±20 μg, most preferably 150±10 μg, and inparticular 150±5 μg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 170±130 μg, more preferably170±100 μg, still more preferably 170±80 μg, yet more preferably 170±60μg, even more preferably 170±40 μg, most preferably 170±20 μg, and inparticular 170±10 μg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 200±175 μg, more preferably200±150 μg, still more preferably 200±125 μg, yet more preferably200±100 μg, even more preferably 200±75 μg, most preferably 200±50 μg,and in particular 200±25 μg.

In still a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 400±350 μg, more preferably400±300 μg, still more preferably 400±250 μg, yet more preferably400±200 μg, even more preferably 400±150 μg, most preferably 400±100 μg,and in particular 400±50 μg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 600±400 μg, more preferably600±300 μg, still more preferably 600±250 μg, yet more preferably600±200 μg, even more preferably 600±150 μg, most preferably 600±100 μg,and in particular 600±50 μg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 800±550 μg, more preferably800±400 μg, still more preferably 800±350 μg, yet more preferably800±250 μg, even more preferably 800±150 μg, most preferably 800±100 μg,and in particular 800±50 μg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 1,000±800 μg, more preferably1,000±600 μg, still more preferably 1,000±500 μg, yet more preferably1,000±300 μg, even more preferably 1,000±200 μg, most preferably1,000±100 μg, and in particular 1,000±50 μg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 1,200±1,000 μg, more preferably1,200±800 μg, still more preferably 1,200±600 μg, yet more preferably1,200±400 μg, even more preferably 1,200±200 μg, most preferably1,200±100 μg, and in particular 1,200±50 μg.

Preferably, the pharmaceutical dosage form according to the inventioncontains the second pharmacologically active ingredient in a dose offrom 10 mg to 7,500 mg, more preferably, 20 mg to 6,000 mg, still morepreferably 50 mg to 5,000 mg, most preferably 80 mg to 4,000 mg, and inparticular 100 mg to 3,000 mg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains the second pharmacologically active ingredient ina dose within the range of 150±125 mg, more preferably 150±100 mg, mostpreferably 150±75 mg, and in particular 150±50 mg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 300±250 mg, more preferably300±200 mg, still more preferably 300±150 mg, yet more preferably300±125 mg, even more preferably 300±100 mg, most preferably 300±75 mg,and in particular 300±50 mg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 500±400 mg, more preferably500±300 mg, still more preferably 500±200 mg, yet more preferably500±150 mg, even more preferably 500±100 mg, most preferably 500±75 mg,and in particular 500±50 mg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 750±500 mg, more preferably750±400 mg, still more preferably 750±250 mg, yet more preferably750±100 mg, even more preferably 750±75 mg, most preferably 750±50 mg,and in particular 750±25 mg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 1,000±500 mg, more preferably1,000±400 mg, still more preferably 1,000±250 mg, yet more preferably1,000±100 mg, even more preferably 1,000±75 mg, most preferably 1,000±50mg, and in particular 1,000±25 mg.

In still a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 1,500±500 mg, more preferably1,500±400 mg, still more preferably 1,500±250 mg, yet more preferably1,500±100 mg, even more preferably 1,500±75 mg, most preferably 1,500±50mg, and in particular 1,500±25 mg.

In yet a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 1,800±1,000 mg, more preferably1,800±750 mg, still more preferably 1,800±500 mg, yet more preferably1,800±300 mg, even more preferably 1,800±200 mg, most preferably1,800±100 mg, and in particular 1,800±50 mg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 2,000±1,000 mg, more preferably2,000±750 mg, still more preferably 2,000±500 mg, yet more preferably2,000±300 mg, even more preferably 2,000±200 mg, most preferably2,000±100 mg, and in particular 2,000±50 mg.

In a preferred embodiment, the pharmaceutical dosage form containsibuprofen as the second pharmacologically active ingredient in a dosewithin the range of 200 mg to 3,200 mg, more preferably in the range of350 mg to 2,750 mg, even more preferably in the range of 500 mg to 2,500mg, still more preferably in the range of 650 mg to 2,200 mg, mostpreferably in the range of 800 mg to 1,850 mg and in particular in therange of 1,000 mg to 1,500 mg.

In the pharmaceutical dosage form according to the invention, the doseof the first pharmacologically active ingredient is preferably withinthe range of from 1:20 to 20:1 of the amount which is equieffective tothe dosage of the second pharmacologically active ingredient. In thisregard, “equieffective” preferably means the dosage that would berequired in order to achieve the equivalent desired therapeutic effectwhen being administered alone. A skilled person recognizes that when thedesired therapeutic effect is an analgesic effect, the equieffectivedosage is determined with respect to the analgesic properties of thefirst pharmacologically active ingredient and the second pharmacologicalingredient.

For example, when the dose of the second pharmacologically activeingredient, which is contained in the pharmaceutical dosage formaccording to the invention, amounts to e.g. 30 mg and provides ananalgesic effect E when being administered alone at this dose, and whenthe equieffective amount of the first pharmacologically activeingredient, i.e. the amount needed in order to provide the sameanalgesic effect E when being administered alone, would be e.g. 4 μg,the dosage of the first pharmacologically active ingredient, which iscontained in the pharmaceutical dosage form according to the invention,may vary from 0.2 μg (4 μg/20) to 80 μg (20.4 μg).

In a preferred embodiment, the dose of the first pharmacologicallyactive ingredient is within the range of from 1:15 to 15:1, preferablywithin the range of from 1:10 to 10:1, more preferably within the rangeof from 1:8 to 8:1, still more preferably within the range of from 1:6to 6:1, yet more preferably within the range of from 1:4 to 4:1, mostpreferably within the range of from 1:3 to 3:1, and in particularpreferably within the range of from 1:2 to 2:1, of the amount which isequieffective to the dose of the second pharmacologically activeingredient.

Suitable pathways of administration of the pharmaceutical dosage formaccording to the invention include but are not limited to oral,intravenous, intraperitoneal, intradermal, transdermal, intrathecal,intramuscular, intranasal, transmucosal, subcutaneous, local and/orrectal administration.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for oral administration.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for parenteral, in particular intravenous,intraperitoneal, intrathecal, intramuscular or subcutaneousadministration.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for rectal administration.

The pharmaceutical dosage form according to the invention and thepharmaceutical composition according to the invention, respectively, canbe solid, semi-solid or liquid.

The pharmaceutical dosage form according to the invention and thepharmaceutical composition according to the invention, respectively, maycontain auxiliary agents, for example, carriers, fillers, solvents,diluents, colorants and/or binders. The selection of auxiliary agentsand of the amounts of the same to be used depends, for example, on howthe first and the second pharmacologically active ingredient are to beadministered, e.g. orally, intravenously, intraperitoneally,intradermally, transdermally, intrathecally, intramuscularly,intranasally, transmucosally, subcutaneously, rectally or locally.

Suitable auxiliary agents are in particular any substances known to aperson skilled in the art useful for the preparation of galenical dosageforms. Examples of suitable auxiliary agents include but are not limitedto: water, ethanol, 2-propanol, glycerol, ethylene glycol, propyleneglycol, polyethylene glycol, polypropylene glycol, glucose, fructose,lactose, saccharose, dextrose, molasses, starch, modified starch,gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose,methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac,cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural andsynthetic gums, acacia gum, alginates, dextran, saturated andunsaturated fatty acids, stearic acid, magnesium stearate, zincstearate, glycerol stearate, sodium lauryl sulphate, edible oils, sesameoil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate,polyoxyethylene and polypropylene fatty acid ester, sorbitan fatty acidester, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannicacid, sodium chloride, potassium chloride, magnesium chloride, calciumchloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide,titanium dioxide, magnesium sulphate, zinc sulphate, calcium sulphate,potash, calcium phosphate, dicalcium phosphate, potassium bromide,potassium iodide, talcum, kaolin, pectin, crosspovidone, agar andbentonite.

Pharmaceutical dosage forms which are suitable for oral administrationinclude but are not limited to tablets, effervescent tablets, chewingtablets, dragees, capsules, drops, juices and syrups. Oralpharmaceutical dosage forms may also be in the form of multiparticulatessuch as granules, pellets, spheres, crystals and the like, optionallycompressed into a tablet, filled into a capsule, filled into a sachet orsuspended in a suitable liquid medium. Oral pharmaceutical dosage formsmay also be equipped with an enteric coating.

Pharmaceutical dosage forms that are suitable for parenteral, topicaland inhalative administration include but are not limited to solutions,suspensions, easily reconstitutable dry preparations and sprays.

Suppositories are a suitable pharmaceutical dosage form for rectaladministration. Dosage forms in a deposit, in dissolved form, forexample, in a patch optionally with the addition of agents to promoteskin penetration, are examples of suitable dosage forms for percutaneousadministration.

In an especially preferred embodiment, the pharmaceutical dosage formaccording to the invention is a tablet.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for administration six times daily, five times daily,four times daily, thrice daily, twice daily, once daily, or lessfrequently.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration twice daily.

In still another preferred embodiment, particularly when the secondpharmacologically active ingredient is ibuprofen, the pharmaceuticaldosage form according to the invention is for administration multipledaily, in particular twice daily, thrice daily, or up to six times aday.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration thrice daily.

For the purpose of specification, “administration thrice daily” (tid)preferably means that the pharmaceutical dosage form according to theinvention is adapted for being consecutively administered according to aregimen comprising the administration of three pharmaceutical dosageforms per day, wherein the time interval between the consecutiveadministration of two pharmaceutical dosage forms is at least 3 hours,preferably at least 4 hours, more preferably not least 6 hours and inparticular, about 8 hours.

For the purpose of specification, “administration twice daily” (bid)preferably means that the pharmaceutical dosage form according to theinvention is adapted for being consecutively administered according to aregimen comprising the administration of two pharmaceutical dosage formsper day, wherein the time interval between the consecutiveadministration of two pharmaceutical dosage forms is at least 6 hours,preferably at least 8 hours, more preferably at least 10 hours and inparticular, about 12 hours.

For the purpose of specification, “administration once daily” (sid)preferably means that the pharmaceutical dosage form according to theinvention is adapted for being consecutively administered according to aregimen comprising the administration of one pharmaceutical dosage formper day, wherein the time interval between the consecutiveadministration of two pharmaceutical dosage forms is at least 18 hours,preferably at least 20 hours, more preferably at least 22 hours and inparticular, about 24 hours.

A skilled person is fully aware that the above administration regimensmay be realized by administering a single pharmaceutical dosage formcontaining the full amount of the first pharmacologically activeingredient and the full amount of the second pharmacologically activeingredient to be administered at a particular point in time or,alternatively, administering a multitude of dose units, i.e. two, threeor more dose units, the sum of which multitude of dose units containingthe full amount of the first pharmacologically active ingredient and thesecond pharmacologically active ingredient to be administered at saidparticular point in time, where the individual dose units are adaptedfor simultaneous administration or administration within a short periodof time, e.g. within 5, 10 or 15 minutes.

In the following, the doses of the first and the secondpharmacologically active ingredient are expressed according to thenumber of prescribed administrations “n” per day, i.e. the number ofadministrations of the pharmaceutical dosage form according to theinvention in the course of 24 hours. As an example, 100/n μg in case ofan administration once daily (n=1) corresponds to a dose of 100 μg, and100/n μg in case of an administration twice daily (n=2) corresponds to adose of 50 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for administration once daily (n=1), wherein thepharmaceutical dosage form contains the first pharmacologically activeingredient in a dose of from 15/n to 100/n μg, preferably 20/n to 80/nμg, and the second pharmacologically active ingredient in a dose of from50/n to 2,500/n mg. According to this embodiment, the pharmaceuticaldosage form according to the invention is preferably for oraladministration, preferably in form of a tablet.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration multiple daily (n=2, 3,4, 5 or 6), wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of from 15/n to 100/n μg,preferably 20/n to 80/n μg, and the second pharmacologically activeingredient in a dose of from 50/n to 2,500/n mg. According to thisembodiment, the pharmaceutical dosage form according to the invention ispreferably for oral administration, preferably in form of a tablet.Further, according to this embodiment, a thrice daily administration canbe especially preferred since the preferred doses of the secondpharmacologically active ingredient may be as high as 2,500/n mg, thusrendering a tablet containing e.g. a maximum of 2,500/3 mg of the secondpharmacologically active ingredient much more patient compliant.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration once daily (n=1),wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of from 150/n to 1,200/nμg, preferably 200/n to 800/n μg, and the second pharmacologicallyactive ingredient in a dose of from 50/n to 2,500/n mg. According tothis embodiment, the pharmaceutical dosage form according to theinvention is preferably for oral administration, preferably in form of atablet.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration multiple daily (n=2, 3,4, 5 or 6), wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of from 150/n to 1,200/nμg, preferably 200/n to 800/n μg, and the second pharmacologicallyactive ingredient in a dose of from 50/n to 2,500/n mg. According tothis embodiment, the pharmaceutical dosage form according to theinvention is preferably for oral administration, preferably in form of atablet. Further, according to this embodiment, a thrice dailyadministration can be especially preferred since the preferred doses ofthe second pharmacologically active ingredient may be as high as 2,500/nmg, thus rendering a tablet containing e.g. a maximum of 2,500/3 mg ofthe second pharmacologically active ingredient much more patientcompliant.

The pharmaceutical dosage form according to the invention may provideunder in vitro conditions immediate release or controlled release of thefirst pharmacologically active ingredient and/or the secondpharmacologically active ingredient. In vitro release is preferablydetermined in accordance with Ph. Eur., preferably paddle method withsinker, 75 rpm, 37° C., 900 mL artificial gastric juice, pH 6.8.

The first pharmacologically active ingredient and/or the secondpharmacologically active ingredient may independently of one another bepresent in the pharmaceutical dosage form at least partially incontrolled-release form. For example, the first pharmacologically activeingredient and/or the second pharmacologically active ingredient may bereleased from the pharmaceutical dosage form in a prolonged manner, e.g.if administered orally, rectally or percutaneously. Such pharmaceuticaldosage forms are particularly useful for “once-daily” or “twice-daily”preparations, which only have to be taken once a day, respectively,twice a day. Suitable controlled-release materials are well known tothose skilled in the art.

The pharmaceutical dosage form according to the invention providingcontrolled release of the first pharmacologically active ingredientand/or the second pharmacologically active ingredient may be producedusing materials, means, devices and processes that are well known in theprior art of pharmaceutical dosage forms.

In order to obtain a solid pharmaceutical dosage form such as a tablet,for example, the pharmacologically active ingredients of thepharmaceutical composition may be granulated with a pharmaceuticalcarrier, for example conventional tablet ingredients such as cornstarch, lactose, saccharose, sorbitol, talcum, magnesium stearate,dicalcium phosphate or pharmaceutically acceptable gums, andpharmaceutical diluents, for example water, in order to form a solidcomposition that contains the pharmacologically active ingredients inhomogeneous distribution. The term “homogeneous distribution” is takento mean that the pharmacologically active ingredients are distributeduniformly over the entire composition, so that said composition mayeasily be divided into equally effective dose units, such as tablets,pills or capsules and the like. The solid composition is then dividedinto dose units. The tablets or pills of the pharmaceutical compositionaccording to the invention may also be coated or compounded in adifferent manner, in order to provide a dosage form with a controlledrelease.

If one of the pharmacologically active ingredients is to be releasedprior to the other pharmacologically active ingredient, for example atleast 30 minutes or 1 hour beforehand, pharmaceutical dosage formshaving a corresponding release profile may be prepared. An example ofsuch a pharmaceutical dosage form is an osmotically-driven releasesystem for achieving a delayed release of either the first or the secondpharmacologically active ingredient from an inner part (core) of thepharmaceutical dosage form via a coating that itself contains the otherpharmacologically active ingredient which is accordingly releasedearlier. In a release system of this kind, which is particularlysuitable for oral administration, at least part, and preferably all, ofthe surface of the release system, preferably those parts that will comeinto contact with the release medium, is/are semipermeable, preferablyequipped with a semipermeable coating, so the surface(s) is/arepermeable to the release medium, but substantially, preferably entirely,impermeable to the pharmacologically active ingredient contained in thecore, the surface(s) and/or optionally the coating comprising at leastone opening for releasing the pharmacologically active ingredientcontained in the core. Moreover, precisely that/those surface(s) thatis/are in contact with the release medium is/are provided with a coatingcontaining and releasing the other pharmacologically active ingredient.This is preferably taken to mean a system in tablet form comprising arelease opening, a core containing the first or the secondpharmacologically active ingredient, a polymer portion that exertspressure upon swelling, a semipermeable membrane and a coatingcontaining the other pharmacologically active ingredient. Embodimentsand examples of osmotically-driven release systems are, for example,disclosed in U.S. Pat. Nos. 4,765,989, 4,783,337 and 4,612,008.

A further example of a suitable pharmaceutical dosage form is agel-matrix tablet. Suitable examples are provided in U.S. Pat. Nos.4,389,393, 5,330,761, 5,399,362, 5,472,711 and 5,455,046. Particularlysuitable is a retarding matrix dosage form, with an inhomogeneousdistribution of the pharmaceutical composition, whereby, for example,one pharmacologically active ingredient, i.e. the first or the secondpharmacologically active ingredient, is distributed in the outer region(the portion that comes into contact with the release medium mostquickly) of the matrix and the other pharmacologically active ingredientis distributed inside the matrix. On contact with the release medium,the outer matrix layer initially (and rapidly) swells and firstlyreleases the pharmacologically active ingredient contained therein,followed by the significantly (more) controlled release of the otherpharmacologically active ingredient. Examples of a suitable matrixinclude matrices with 1 to 80% by weight of one or more hydrophilic orhydrophobic polymers as pharmaceutically acceptable matrix formers.

Preferably, the pharmaceutical dosage form according to the inventionprovides immediate release of the first pharmacologically activeingredient, and immediate or controlled release of the secondpharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention provides immediate release of both, the first and thesecond pharmacologically active ingredient. In this particular case, amultiple daily administration, in particular an administration twicedaily, thrice daily, or up to six times a day is preferred.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention provides immediate release of the firstpharmacologically active ingredient, and controlled release of thesecond pharmacologically active ingredient. This release profile may berealized by employing the aforementioned methods, e.g. theosmotically-driven release system providing the first pharmacologicallyactive ingredient in the coating and the second pharmacologically activeingredient in the core, or the retarding matrix dosage form containingthe first pharmacologically active ingredient in the outer matrix layerand the second pharmacologically active ingredient in the inside of thematrix.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention provides controlled release of both the firstand the second pharmacologically active ingredient.

In a further aspect, the invention relates to the use of thepharmaceutical composition according to the invention, and thepharmaceutical dosage form according to the invention respectively, inthe prevention or treatment of pain.

In a preferred embodiment, the pharmaceutical composition according tothe invention and the pharmaceutical dosage form according to theinvention, respectively, are for use in the treatment of pain, whereinthe pain is preferably

-   -   peripheral, central or muscle skeletal pain; and/or    -   acute, subacute or chronic pain; and/or    -   moderate to severe pain; and/or    -   neuropathic or psychogenic or nociceptive or mixed pain; and/or    -   low back pain, visceral pain or headache; and/or    -   post-operative (post-surgical), cancer or inflammatory pain.

For the purpose of specification, “acute pain” preferably refers to painthat lasts up to about 4 weeks, “subacute pain” preferably refers topain that lasts from more than about 4 weeks to about 12 weeks, and“chronic pain” preferably refers to pain that lasts for more than about12 weeks.

Preferably, the pain is selected from the group consisting of cancerpain, peripheral neuropathic pain, osteoarthritis, chronic visceralpain, neuropathic pain (diabetic polyneuropathy, HIV-associatedneuropathic pain, posttraumatic neuropathic pain, postherpeticneuralgia, chemotherapy associated pain), postzosteric neuralgia,postoperative neuropathic pain, inflammatory pain, migraine, low-backpain, fibromyalgia and trigeminal neuralgia.

In another preferred embodiment, the pain is chronic pain, in particularchronic nociceptive pain and/or chronic inflammatory pain.

In still another preferred embodiment, the pain is non-chronic or acutepain, in particular postoperative (postsurgical) pain.

In yet another preferred embodiment, the pain is selected from acute ornon-chronic postoperative neuropathic pain and chronic inflammatorypain.

In the following, the doses of the first and the secondpharmacologically active ingredient are again expressed according to thenumber of administrations “n” per day, i.e. the number ofadministrations of the pharmaceutical dosage form according to theinvention in the course of 24 hours.

In a preferred embodiment, the pharmaceutical dosage form is for use inthe treatment of neuropathic pain which may be optionally superimposedby nociceptive pain, where the dose of the first pharmacologicallyactive ingredient contained in the pharmaceutical dosage form preferablyis in the range of 1/n μg to 800/n μg or 1/n μg to 600/n μg or 1/n μg to400/n μg or 1/n μg to 250/n μg, more preferably in the range of 5/n μgto 150/n μg, even more preferably in the range of 10/n μg to 100/n μg,most preferably in the range of 20/n μg to 80/n μg and in particular inthe range of 30/n μg to 50/n μg. According to this embodiment, the doseof the second pharmacologically active ingredient contained in thepharmaceutical dosage form preferably is in the range of 100/n mg to2,500/n mg.

In a preferred embodiment, in particular when the pharmaceutical dosageform is for use in the treatment of neuropathic pain and the secondpharmacologically active ingredient is ibuprofen, the dose of the firstpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 1/n μg to 800/n μg or 1/n μgto 600/n μg or 1/n μg to 400/n μg or 1/n μg to 250/n μg, more preferablyin the range of 5/n μg to 150/n μg, even more preferably in the range of10/n μg to 100/n μg, most preferably in the range of 20/n μg to 80/n μgand in particular in the range of 30/n μg to 50/n μg; and the dose ofthe second pharmacologically active ingredient contained in thepharmaceutical dosage form preferably is in the range of 100/n mg to2,500/n mg, more preferably in the range of 200/n mg to 2,200/n mg, evenmore preferably in the range of 400/n mg to 2,000/n mg, still morepreferably in the range of 600/n mg to 1,800/n mg most preferably in therange of 800/n mg to 1,600/n mg and in particular in the range of1,000/n mg to 1,400/n mg.

In another preferred embodiment, the pharmaceutical dosage form is foruse in the treatment of nociceptive pain which may be optionallysuperimposed by neuropathic pain, where the dose of the firstpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 50/n μg to 2,000/n μg or 50/nμg to 1,400/n μg or 50/n μg to 1,200/n μg or 50/n μg to 1000/n μg, morepreferably in the range of 100/n μg to 800/n μg, still more preferablyin the range of 150/n μg to 650/n μg, even more preferably in the rangeof 250/n μg to 550/n μg, and most preferably in the range of 350/n μg to450/n μg. According to this embodiment, the dose of the secondpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 100/n mg to 2,500/n mg.

In a preferred embodiment, in particular when the pharmaceutical dosageform is for use in the treatment of nociceptive pain and the secondpharmacologically active ingredient is ibuprofen, the dose of the firstpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 50/n μg to 2,000/n μg or 50/nμg to 1,400/n μg or 50/n μg to 1,200/n μg or 50/n μg to 1000/n μg, morepreferably in the range of 100/n μg to 800/n μg, still more preferablyin the range of 150/n μg to 650/n μg, even more preferably in the rangeof 250/n μg to 550/n μg, and most preferably in the range of 350/n μg to450/n μg; and the dose of the second pharmacologically active ingredientcontained in the pharmaceutical dosage form preferably is in the rangeof 100/n mg to 2,500/n mg, more preferably in the range of 200/n mg to2,200/n mg, even more preferably in the range of 400/n mg to 2,000/n mg,still more preferably in the range of 600/n mg to 1,800/n mg mostpreferably in the range of 800/n mg to 1,600/n mg and in particular inthe range of 1,000/n mg to 1,400/n mg.

Preferably, the pharmaceutical composition contains the first and thesecond pharmacologically active ingredient in such a weight ratio thatthey will exert a synergistic therapeutic effect upon administration toa patient. Thereby, the term “synergistic therapeutic effect” refers toa synergistic therapeutic effect with respect to the prevention ortreatment of pain (synergistic analgesic effect). Suitable weight ratiosof the pharmacologically active ingredients generating the synergistictherapeutic effect can be determined by methods well known to thoseskilled in the art.

A further aspect of the invention relates to a method of treating orpreventing pain comprising the preferably twice daily or once daily,preferably oral administration of the pharmaceutical dosage formaccording to the invention to a subject in need thereof.

In a particular preferred embodiment,

-   -   the first pharmacologically active ingredient is        (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine        according to formula (I) in form of its free base, or a        hemicitrate, hydrochloride or maleate salt thereof; and/or    -   the second pharmacologically active ingredient is an aryl        propionic acid derivative selected from the group consisting of        ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen,        suprofen, pirprofen, indoprofen, ibuproxam, flunoxaprofen,        alminoprofen and naproxcinod, and the physiologically acceptable        salts thereof; and/or    -   the pharmaceutical composition and the pharmaceutical dosage        form, respectively, contain the first pharmacologically active        ingredient in a dose of from 20 μg to 80 μg or of from 80 μg to        200 μg or of from 200 μg to 800 μg or of from 800 μg to 1,200        μg; and/or    -   the pharmaceutical composition and the pharmaceutical dosage        form, respectively, contain the second pharmacologically active        ingredient in a dose of from 100 mg to 2,500 mg, and/or    -   the relative weight ratio of the first pharmacologically active        ingredient to the second pharmacologically active ingredient is        within the range of from 1:30 to 1:1,000,000 in the        pharmaceutical composition and the pharmaceutical dosage form,        respectively; and/or    -   the pharmaceutical composition is for use in the prevention or        treatment of pain; and/or    -   the pharmaceutical composition is for use in the treatment of        pain, wherein the pain is peripheral, central or muscle skeletal        pain; and/or acute, subacute or chronic pain; and/or moderate to        severe pain; and/or neuropathic or psychogenic or nociceptive or        mixed pain; and/or low back pain, visceral pain or headache;        and/or post-operative (post-surgical), cancer or inflammatory        pain; and/or    -   the pharmaceutical composition and the pharmaceutical dosage        form, respectively, contain the first pharmacologically active        ingredient and the second pharmacologically active ingredient in        such a weight ratio that upon administration to a patient they        will exert a synergistic therapeutic effect; and/or    -   the pharmaceutical dosage form provides immediate release of the        first pharmacologically active ingredient in vitro in accordance        with Ph. Eur.; and/or    -   the pharmaceutical dosage form provides immediate or controlled        release of the second pharmacologically active ingredient in        vitro in accordance with Ph. Eur.; and/or    -   the pharmaceutical dosage form is for oral administration;        and/or    -   the pharmaceutical dosage form is for administration once, twice        or thrice daily.

In a further aspect, the invention relates to a kit comprising a firstpharmaceutical dosage form comprising the first pharmacologically activeingredient as described above, and a second pharmaceutical dosage formcomprising the second pharmacologically active ingredient as describedabove.

A suitable embodiment is a kit in which the first pharmaceutical dosagefrom comprising the first pharmacologically active ingredient and thesecond pharmaceutical dosage form comprising the secondpharmacologically active ingredient, although spatially separated, areprovided in a common presentation form, e.g. packaging.

Preferably, the first and the second pharmaceutical dosage form areadapted for simultaneous or sequential administration, wherein the firstpharmaceutical dosage form may be administered before or after thesecond pharmaceutical dosage form and wherein the first and the secondpharmaceutical dosage form are administered either via the same or adifferent pathway of administration.

For the purpose of specification, the term “simultaneous administration”preferably refers to an administration of the first and the secondpharmaceutical dosage form within a time span of 15 minutes from eachother, whereas the term “sequential administration” preferably refers toan administration of the first and the second pharmaceutical dosage formwithin a time span of more than 15 minutes from each other.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are adapted for administration to the patient via the samepathway.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are adapted for administration to the patient via differentpathways.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are administered simultaneously.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are administered sequentially.

In a preferred embodiment, the first and/or the second pharmaceuticaldosage form are adapted for once daily administration.

In another preferred embodiment, the first and/or the secondpharmaceutical dosage form are adapted for multiple dailyadministration, in particular twice daily or thrice daily.

In a preferred embodiment, the first pharmaceutical dosage form isadapted for once daily administration and the second pharmaceuticaldosage form is adapted for multiple daily, in particular twice daily orthrice daily, administration.

Suitable pathways of administration of the pharmaceutical dosage formscontained in the kit include but are not limited to oral, intravenous,intraperitoneal, intradermal, intrathecal, intramuscular, intranasal,transmucosal, subcutaneous, and/or rectal administration.

In a preferred embodiment, one or both of the pharmaceutical dosageforms contained in the kit are for oral administration.

In another preferred embodiment, one or both of the pharmaceuticaldosage forms contained in the kit are for parenteral, in particularintravenous, intraperitoneal, intrathecal, intramuscular or subcutaneousadministration.

In still another preferred embodiment, one or both of the pharmaceuticaldosage forms contained in the kit are for rectal administration.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are for oral, simultaneous administration once daily.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are for oral, simultaneous administration multiple daily, inparticular twice daily or thrice daily.

In still another preferred embodiment, the first and the secondpharmaceutical dosage form are each for oral, sequential administrationonce daily.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are for sequential administration once daily each, where thefirst and the second pharmaceutical dosage form are adapted foradministration via different pathways, e.g. oral and parenteral orrectal administration.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are each for oral, sequential administration multiple daily,in particular twice daily or thrice daily.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are for sequential administration multiple daily each, inparticular twice daily or thrice daily, where the first and the secondpharmaceutical dosage form are adapted for administration via differentpathways, e.g. oral and parenteral or rectal administration.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

Pharmacological Methods

In the following, the first pharmacologically active ingredient(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminewas employed in form of the hemicitrate salt. Therefore, all amounts ofthe first pharmacologically active ingredient are specified with respectto the hemicitrate salt.

As the second pharmacologically active ingredient, ibuprofen wasemployed.

EXAMPLE 1 Paw Incision Model in Rats (Postoperative Pain)

The experiments were carried out in male albino rats (Sprague Dawley)with 170 g-230 g body weight from a commercial breeder (Janvier;France). The animals were housed under standardized conditions:light/dark rhythm (06.00 h-18.00 h light, 18.00 h-06.00 h dark); roomtemperature 20° C.-24° C.; relative air humidity 35%-70%; 15 air changesper hour, air movement <0.2 m/sec. The animals were given tap water anda diet of standard laboratory food (Ssniff R/M-Haltung, SsniffSpezialdiäten GmbH, Soest, Germany) ad libitum. Both were withdrawnduring the test. All rats were used only once. Ten rats were used perexperimental group. There were at least five days between delivery ofthe animals and the day of surgery.

The rats were placed in a plastic cage with a wire mesh bottom whichallowed full access to the paws. Hind paw withdrawal threshold aftermechanical stimulation was tested with electronic von Frey hairs(Somedic Sales AB, Hörby, Sweden). Animals were placed in a plastic cagewith a wire mesh bottom which allowed full access to the paws.Behavioral accommodation was allowed for 30 min. In each case,withdrawal response was measured at an area adjacent to the wound(ipsilateral) and to the same area on the non-injured foot(contralateral). Two hours after surgery, primary hypersensitivity wastested as tactile withdrawal threshold shortly before drugadministration and at different time points after drug application.Animals injected with vehicle served as controls. The pretestmeasurement was made prior to surgery and two thresholds were taken pertest and averaged.

Surgery was performed as previously described (Brennan T. J.,Vandermeulen E. P., and Gebhart G. F., Characterization of a rat modelof incisional pain, Pain 1996; 64:493-501). Briefly, rats wereanaesthetised with isoflurane, and a 1 cm longitudinal incision wasmade, through skin and fascia of the plantar aspect of the foot,starting from the proximal edge of the heel and extending toward themetatarsal toes. The plantaris muscle was elevated and incisedlongitudinally. The muscle origin and insertion remained intact. Afterspreading of the muscle and haemostasis with gentle pressure, the skinwas closed with two single interrupted sutures. After surgery, the ratswere allowed to recover in their home cages and the animals regainedconsciousness within 2 to 5 minutes. In order to ensure a completerecovery from anaesthesia the baseline value of each individual animalwas recorded not until 2 hours after surgery.

The first pharmacologically active ingredient was dissolved in 5% DMSOand 95% glucose solution (5%). The second pharmacologically activeingredient was dissolved in 1% CMC in aqua dest. Intravenous (i.v.) andintraperitoneal (i.p.) applications were made in a volume of 5 mL/kg.

Data were recorded and the median was calculated from five values ofeach animal and measurement.

The median values of the individual latencies are calculated as thepercentage of the Maximum Possible Effect (% MPE) according to thefollowing formula:% MPE=100−[(value after application−pretest before surgery)/(pretestafter surgery−pretest before surgery)−100]

The individual % MPE values were averaged for the respective treatmentgroup and expressed as mean % MPE ±standard error of the mean (SEM).

The pharmacologically active ingredients were administered using alogarithmically staggered dose scheme. The results are presented ingraphs as means±SEM against the time after surgery.

Data were analyzed by means of two-factor analysis of variance (ANOVA)with repeated measures. Significance of treatment-, time- or treatment xtime interaction effects was analyzed by means of Wilks' Lambdastatistics. In case of a significant treatment effect, pair-wisecomparison was performed at the different time points effect by Fisher'sleast significant difference test. Results were considered statisticallysignificant if p<0.05.

ED₂₅ values were determined by regression analysis in case ofdose-dependent results (according to Litchfield J. T. and Wilcoxon F.A., A simplified method of evaluating dose-effect experiments, J.Pharmacol. Exp. Ther. 1949; 96: 99-113). The analysis of the resultswith respect to a supra-additive effect of the of the first and thesecond pharmacologically active ingredient according to the invention iscarried out via statistical comparison of the theoretical additiveED₂₅-value or by comparison of the theoretically additive effect ofdefined doses of the first and the second pharmacologically activeingredient with the experimental determined effect of their combination.If an ED₂₅-value could be calculated, a statistical comparison of thetheoretical ED₂₅-value with the experimentally determined ED₂₅-value ofa so-called fixed ratio combination was carried out (isobolographicanalysis according to Tallarida J. T., Porreca F., and Cowan A.,Statistical analysis of drug-drug and site-site interactions withisobolograms, Life Sci. 1989; 45: 947-961).

The interaction studies presented herein were performed usingequieffective doses of the first and the second pharmacologically activeingredient, calculated from the ratio of the respective ED₂₅ values ofthe first and the second pharmacologically active ingredient ifadministered alone.

The application route was intravenous (i.v.) for the firstpharmacologically active ingredient and intraperitoneal (i.p.) for thesecond pharmacologically active ingredient.

Tests were performed using doses of 0.001 mg/kg body weight to 0.01mg/kg body weight of the first pharmacologically active ingredient and21.5 mg/kg body weight to 147 mg/kg body weight of the secondpharmacologically active ingredient.

The second pharmacologically active ingredient ibuprofen wasadministered 30 min. prior to the first pharmacologically activeingredient.

The time point of ED₂₅ calculation in case of the combinedadministration of the first and the second pharmacologically activeingredient according to the invention corresponds to the timepoint ofthe peak effect of the respective pharmacologically active ingredient.The isobolographic analysis revealed that the experimental ED₂₅-valuesregarding the combined administration of the first and the secondpharmacologically active ingredient were significantly lower than therespective theoretical ED₂₅-values and the effect of other experimentswith fixed dose combinations showed higher experimental determinedefficacy than the theoretically calculated efficacy. Thus, thecombination studies demonstrate significant synergistic interaction ofthe first pharmacologically active ingredient with the secondpharmacologically active ingredient.

When administered as a combination, the first and the secondpharmacologically active ingredient showed a dose dependent analgesicefficacy. At a dose ratio of 1:16,757, combined administration of thefirst pharmacologically active ingredient (0.010 mg/kg body weight i.v.)and the second pharmacologically active ingredient (147 mg/kg bodyweight i.p.) resulted in a maximal effect of 66% MPE at 30 min. afteradministration of the first pharmacologically active ingredient.

The results are summarized in FIGS. 1 and 2 and tables 1 to 5.

FIG. 1 shows the withdrawal threshold in g in dependence of the timeelapsed after administration.

dose [mg/kg] ●  0.0 + 0.0 vehicle ◯ 0.001 + 21.5 ▴ 0.003 + 46.4 firstpharmacologically active ingredient +

0.006 + 100  {close oversize brace} second pharmacologically activeingredient ▪ 0.010 + 147  _(——) ipsilateral ----- contralateral OP:operation

FIG. 2 shows the graphical analysis of experimental ED₂₅-valuescorresponding to the single administration of the firstpharmacologically active ingredient and ibuprofen as the secondpharmacologically active ingredient, respectively, and the correspondingtheoretic additive values for the combined administration of the firstand the second pharmacologically active ingredient compared to theexperimental ED₂₅-values determined for said combination.

ED₂₅ (95% CI) [mg/kg] (i.v./i.p.) first pharmacologically active 0.0065(0.0057-0.0072) ingredient = second pharmacologically active 117(90.1-196) ingredient = ▪ theoretical additive value = 56.3 (42.7-70.0)part of first pharmacologically active 0.0034 (0.0026-0.0042) ingredient= part of second pharmacologically active 56.3 (42.7-70.0) ingredient =● experimental value of the combined = 30.6 (21.8-38.6) administrationof the first and the second pharmacologically active ingredient part offirst pharmacologically active 0.0018 (0.0016-0.0020) ingredient = partof second pharmacologically active 30.6 (15.3-45.9) ingredient =

TABLE 1 data corresponding to FIG. 1 % MPE (Maximum possible effect) ofthe combined administration of the first and the secondpharmacologically active ingredient in dependence of the time postadministration and isobolographic analysis of the interaction betweenthe first and the second pharmacologically active ingredient: % MPE 30min. (n = 60 min. (n = 90 min. (n = dose 10) 10) 10) [mg/kg] Mean SEMMean SEM Mean SEM vehicle  0.0 + 0.0 −1.76 ± 0.97 −1.5 ± 0.63 −0.64 ±1.68  first 0.001 + 21.5  19.0 ± 2.46 5.55 ± 1.41 2.21 ± 1.07 pharma- p≦ 0.001 n.s. n.s. cologically 0.003 + 46.4  35.0 ± 4.05 18.2 ± 2.79 9.56± 2.13 active p ≦ 0.001 p ≦ 0.001 p ≦ 0.001 ingredient + 0.006 + 100  39.0 ± 4.01 12.2 ± 2.66 10.3 ± 2.64 second p ≦ 0.001 p ≦ 0.001 p ≦0.001 pharma- 0.010 + 147   66.2 ± 3.15 36.2 ± 3.82 25.4 ± 2.44cologically p ≦ 0.001 p ≦ 0.001 p ≦ 0.001 active ingredient p: level ofstatistical significance. n.s.: not significant.

TABLE 2 data corresponding to FIG. 1 ipsilateral: GLM Repeated Measuresand Statistical evaluation of the data following two-factor analysis ofvariance (ANOVA) and Fisher's LSD: GLM (General Linear Model)ipsilateral treatment time interaction F(4, 45) = 69.446 F(2, 90) =138.450 F(8, 90) = 14.100 p < 0.001 p < 0.001 p < 0.001 ANOVA [Fisher'sLSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.001 + 21.5 p < 0.001 p =0.109 p = 0.570 0.003 + 46.4 p < 0.001 p < 0.001 p = 0.014 0.006 + 100 p< 0.001 p = 0.002 p = 0.002 0.010 + 147 p < 0.001 p < 0.001 p < 0.001 p:level of statistical significance.

TABLE 3 data corresponding to FIG. 1 contralateral: GLM RepeatedMeasures and Statistical evaluation of the data following two- factoranalysis of variance (ANOVA) and Fisher's LSD: GLM (General LinearModel) contralateral treatment time interaction F(4, 45) = 19.623 F(2,90) = 25.334 F(8, 90) = 8.826 p < 0.001 p < 0.001 p < 0.001 ANOVA[Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.001 + 21.5 p =0.627 p = 0.554 p = 0.883 0.003 + 46.4 p = 0.909 p = 0.882 p = 0.2040.006 + 100  p = 0.069 p = 0.519 p = 0.334 0.010 + 147  p < 0.001 p =0.029 p < 0.001 p: levelof statistical significance.

TABLE 4 ED₂₅ values of the first and the second pharmacologically activeingredient and isobolographic analysis of the interaction between thefirst and the second pharmacologically active ingredient: Substance/ED₂₅[mg/kg] (confidence interval) Theoretical Experimental first second ED₂₅[mg/kg] of ED₂₅ [mg/kg] of pharmacologically pharmacologically thecombined the combined active ingredient active ingredient administrationadministration Interaction 0.0065 (0.0057-0.0072) 117 (90.1-196) 56.330.6 supra- (42.7-70.0) (21.8-38.6) additive (p < 0.001) p: level ofstatistical significance.

TABLE 5 data corresponding to FIG. 2 % MPE: GLM Repeated Measures andStatistical evaluation of the data following two-factor analysis ofvariance (ANOVA) and Fisher's LSD: GLM (General Linear Model) % MPEtreatment time interaction F(4, 45) = 75.033 F(2, 90) = 138.640 F(8, 90)= 13.978 p < 0.001 p < 0.001 p < 0.001 ANOVA [Fisher's LSD] dose [mg/kg]30 min. 60 min. 90 min. 0.001 + 21.5 p < 0.001 p = 0.055 p = 0.3350.003 + 46.4 p < 0.001 p < 0.001 p = 0.001 0.006 + 100 p < 0.001 p <0.001 p < 0.001 0.010 + 147 p < 0.001 p < 0.001 p < 0.001 p: level ofstatistical significance.

EXAMPLE 2 Randall Selitto Test in Rats

The weight ratios of the first and the second pharmacologically activeingredient that will lead to a supra-additive effect (synergisticeffect) may be determined via the test of Randall and Selitto asdescribed in Arch. Int. Pharmacodyn., 1957, 111: 409-419, which is amodel for inflammatory pain. The respective part of the literature ishereby incorporated by reference and forms part of the presentdisclosure.

By means of injection of 0.1 ml of Carrageenin-suspension ventrally intoa hind paw of a rat an oedema is induced, on which pain is generated 4hours later by continuously increasing pressure with a stamp (2 mm tipdiameter). The antinociceptive and antihyperalgesic activity of thetested pharmacologically active ingredient is determined at differentpoints in time after administration of the pharmacologically activeingredient. The measured value to be determined and at the same timealso the end point of the pain test is the pressure at which thevocalisation reaction of the rat occurs. The percentage maximum possibleeffect (% MPE) is calculated. The maximum pressure of the stamp is 250g. The group size is n=12.

ED₅₀ values were determined by regression analysis in case ofdose-dependent results (according to Litchfield J. T. and Wilcoxon F.A., A simplified method of evaluating dose-effect experiments, J.Pharmacol. Exp. Ther. 1949; 96: 99-113). The analysis of the resultswith respect to a supra-additive effect of the first and the secondpharmacologically active ingredient is carried out via statisticalcomparison of the theoretical additive ED₅₀-value with theexperimentally determined ED₅₀-value of a so-called fixed ratiocombination (isobolographic analysis according to Tallarida J. T.,Porreca F., and Cowan A., Statistical analysis of drug-drug andsite-site interactions with isobolograms, Life Sci. 1989; 45: 947-961).

The interactions studies presented herein were performed usingequieffective doses of the first and the second pharmacologically activeingredient, calculated from the ratio of the respective ED₅₀ values ofthe first and the second pharmacologically active ingredient ifadministered alone.

The application route was intravenous (i.v.) for the firstpharmacologically active ingredient and intraperitoneal (i.p.) for thesecond pharmacologically active ingredient. The first pharmacologicallyactive ingredient was dissolved in 5% DMSO, 5% Cremophor and 90% glucosesolution (5%). The second pharmacologically active ingredient wasdissolved in 1% CMC in aqua dest. Intraveneous (i.v.) andintraperitoneal (i.p.) applications were made in a volume of 5 ml/kg.

In case of the combined, simultaneous administration, the relative doseratio of first pharmacologically active ingredient to the secondpharmacologically active ingredient was 1:41,937.

When the first pharmacologically active ingredient(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the hemicitrate salt was applied alone, the peak effect wasreached 15 min p. appl. (timepoint of first measurement) correspondingto an ED₅₀-value of 3.31 (2.85-3.75) μg/kg i.v. The secondpharmacologically active ingredient Ibuprofen induced a dose-dependentanalgesic effect with ED₅₀-values of 138,810 (130,305-147,084) μg/kgi.p., reaching the peak effect 30 min p. appl. According to theirrespective timepoint of peak effect, the first pharmacologically activeingredient was applied 15 min and the second pharmacologically activeingredient 30 min before timepoint of measurement of theinteraction-experiments (i.e. the second pharmacologically activeingredient was applied 15 min before the first pharmacologically activeingredient).

Thus, the time point of ED₅₀ calculation in case of the combinedadministration of the first and the second pharmacologically activeingredient according to the invention corresponds to the timepoint ofthe peak effect of the respective pharmacologically active ingredient.The isobolographic analysis revealed that the experimental ED₅₀-valuesregarding the combined administration of the first and the secondpharmacologically active ingredient were significantly lower than therespective theoretical ED₅₀-values. Thus, the combination studiesdemonstrate significant synergistic interaction of the firstpharmacologically active ingredient with the second pharmacologicallyactive ingredient.

The results of the isobolographic analysis are summarized in thefollowing table 6.

FIG. 3 shows the graphical analysis of experimental ED₅₀-valuescorresponding to the single administration of the firstpharmacologically active ingredient and ibuprofen as the secondpharmacologically active ingredient, respectively, and the correspondingtheoretic additive values for the combined administration of the firstand the second pharmacologically active ingredient compared to theexperimental ED₅₀-values determined for said combination.

ED₅₀ (95% CI) [μg/kg] (i.v./i.p.) first pharmacologically active 3.31(2.85-3.75) ingredient = second pharmacologically active 138,810(130,305-147,084) ingredient = ▪ theoretical additive value = 69,407(64,287-74,526) part of first pharmacologically active 1.66 (1.53-1.78)ingredient = part of second pharmacologically 69,405 (64,286-74,524)active ingredient = ● experimental value of the combined = 36,877(29,866-41,500) administration of the first and the secondpharmacologically active ingredient part of first pharmacologically0.879 (0.759-1.0) active ingredient = part of second pharmacologically36,876 (34,647-39,105) active ingredient =

TABLE 6 Experimental ED₅₀ values of the first and the secondpharmacologicall active ingredient and isobolographic analysis of theinteraction between the first and the second pharmacologically activeingredient: Substance/ED₅₀ [μg/kg] (confidence interval) TheoreticalED₅₀ Experimental first second [μg/kg] of the ED₅₀ [μg/kg] ofpharmacologically pharmacologically combined the combined activeingredient active ingredient administration administration Interaction3.31 (2.85-3.75) 138,810 (130,305-147,084) 69,407 (64,287-74,526) 36,877(29,866-41,500) supra- additive (p < 0.001) p: level of statisticalsignificance.

The invention claimed is:
 1. A pharmaceutical composition comprising atherapeutically effective amount to treat acute post-operative pain orchronic inflammatory pain of: a) a first pharmacologically activeingredient, which is selected from the compound according to formula (I)

 and the physiologically acceptable salts thereof, and b) a secondpharmacologically active ingredient, which is ibuprofen or aphysiologically acceptable salt thereof, wherein the relative weightratio of the first pharmacologically active ingredient to the secondpharmacologically active ingredient is within the range of 1:30 to1:1,000,000.
 2. The pharmaceutical composition according to claim 1,wherein the first pharmacologically active ingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine.3. A pharmaceutical dosage form comprising the pharmaceuticalcomposition according to claim
 1. 4. The pharmaceutical dosage formaccording to claim 3, which contains the first pharmacologically activeingredient in a dose of 10 to 1,200μg.
 5. The pharmaceutical dosage formaccording to claim 3, which contains the second pharmacologically activeingredient in a dose of 0.05 to 5 g.
 6. The pharmaceutical dosage formaccording to claim 3, wherein the dosage of the first pharmacologicallyactive ingredient is within the range of 1:20 to 20:1 of the amountwhich is equieffective to the dosage of the second pharmacologicallyactive ingredient.
 7. The pharmaceutical dosage form according to claim3, which is for oral, intravenous, intraperitoneal, transdermal,intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, orrectal administration.
 8. The pharmaceutical dosage form according toclaim 3, which provides under in vitro conditions immediate release orcontrolled release of the first pharmacologically active ingredient, thesecond pharmacologically active ingredient, or both.
 9. A kit comprisinga first pharmaceutical dosage form comprising the firstpharmacologically active ingredient as defined in claim 1, a secondpharmaceutical dosage form comprising the second pharmacologicallyactive ingredient as defined in claim 1, and packaging.
 10. The kitaccording to claim 9, wherein the first pharmaceutical dosage form andthe second pharmaceutical dosage form are adapted for simultaneous orsequential administration, either by the same or a different pathway ofadministration.
 11. A method of treating acute post-operative pain orchronic inflammatory pain, comprising administering a pharmaceuticaldosage form comprising a pharmaceutical composition to a subject in needthereof, wherein the pharmaceutical composition comprises atherapeutically effective amount to treat acute post-operative pain orchronic inflammatory pain of: a) a first pharmacologically activeingredient, which is selected from the compound according to formula (I)

 and the physiologically acceptable salts thereof, and b) a secondpharmacologically active ingredient, which is ibuprofen or aphysiologically acceptable salt thereof, wherein the relative weightratio of the first pharmacologically active ingredient to the secondpharmacologically active ingredient is within the range of 1:30 to1:1,000,000.
 12. The method according to claim 11, wherein the acutepost-operative pain or the chronic inflammatory pain is peripheral pain,central pain, or muscle skeletal pain.
 13. The method according to claim11, wherein the acute post-operative pain or the chronic inflammatorypain is moderate to severe pain.
 14. The method according to claim 11,wherein the acute post-operative pain or the chronic inflammatory painis neuropathic pain, psychogenic pain, nociceptive pain, or mixed pain.15. The method according to claim 11, wherein the acute post-operativepain or the chronic inflammatory pain is low back pain, visceral pain,or headache.
 16. The method according to claim 11, wherein the firstpharmacologically active ingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]-indol]-4-amine.17. The method according to claim 11, wherein the pharmaceuticalcomposition contains the first pharmacologically active ingredient andthe second pharmacologically active ingredient in such a weight ratiothat they will exert a synergistic therapeutic effect uponadministration to a patient.
 18. The method according to claim 11,wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of 10 to 1,200 μg.
 19. Themethod according to claim 11, wherein the pharmaceutical dosage formcontains the second pharmacologically active ingredient in a dose of0.05 to 5 g.
 20. The method according to claim 11, wherein, in thepharmaceutical dosage form, the dosage of the first pharmacologicallyactive ingredient is within the range of 1:20 to 20:1 of the amountwhich is equieffective to the dosage of the second pharmacologicallyactive ingredient.
 21. The method according to claim 11, wherein thepharmaceutical dosage form is for oral, intravenous, intraperitoneal,transdermal, intrathecal, intramuscular, intranasal, transmucosal,subcutaneous, or rectal administration.
 22. The method according toclaim 11, wherein the pharmaceutical dosage form provides under in vitroconditions immediate release or controlled release of the firstpharmacologically active ingredient, the second pharmacologically activeingredient, or both.
 23. A pharmaceutical composition comprising atherapeutically effective amount to treat acute post-operative pain orchronic inflammatory pain of: a) a first pharmacologically activeingredient, which is selected from(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4,b]indol]-4-amineand the physiologically acceptable salts thereof, and b) a secondpharmacologically active ingredient, which is ibuprofen or aphysiologically acceptable salt thereof, wherein the firstpharmacologically active ingredient and the second pharmacologicallyactive ingredient are present in such a weight ratio that they willexert a synergistic therapeutic effect upon administration to a patient.